PROJECT SUMMARY/ABSTRACT The use of target-directed synthesis as inspiration for the discovery of novel reactions gives access to new, medicinally relevant structures and general methods for their synthesis, as well as new synthetic methodologies that will benefit an array of diverse applications. Ultimately, any development that enhances our ability to assemble compounds more efficiently will have a profound impact upon biology and human medicine through medicinal chemistry and process research and development. This application describes the development of a novel reaction methodology for the enantioselective formation of vicinal quaternary and tertiary stereocenters. Specifically, the research strategy exploits this methodology to outline a synthetic route to the natural product isopalhinine A. Isopalhinine A is a Lycopodium alkaloid with the most sterically congested and structurally complex framework of all the members of the family. Since its isolation in 2013, no completed synthesis has been reported to date. In this multifaceted and integrated program, we hypothesize that expanding the scope of our laboratory's recently developed iridium-catalyzed allylic alkylation chemistry from aryl- and alkenyl-substituted allyl carbonates to include alkyl-substituted electrophiles will facilitate a concise, enantioselective synthesis of isopalhinine A. The specific aims of this application are: 1) the expansion of iridium-catalyzed asymmetric allylic alkylation chemistry with prochiral carbon nucleophiles to include alkyl-substituted electrophiles, 2) total synthesis of isopalhinine A: construction of the spirocyclic intermediate, and 3) total synthesis of isopalhinine A: intramolecular Diels-Alder reaction and final modifications. The described expansion in the field of iridium-catalyzed allylic alkylation chemistry as well as the additional innovation embedded within the strategies and tactics employed in the total synthesis will ultimately lead to the more efficient assembly of other complex bioactive targets and, broadly, the discovery of new therapeutics.